Process for preparing benzhydrylthioacetamide

ABSTRACT

The present invention is directed to an improved process for preparing modafinil wherein benzhydrylthioacetamide is prepared in high yield and purity by the reaction of a haloacetamide with the reaction product of thiourea and benzhydrol in aqueous solution. The reaction employing the haloacetamide is conducted in a solvent comprising water and an organic solvent such as dimethylformamide having dissolved therein a basic salt such as potassium carbonate. The resulting benzhydrylthioacetamide can be oxidized to provide the pharmaceutical modafinil.

This invention relates to an improved process for preparing modafinilwherein the intermediate, benzhydrylthioacetamide, is prepared in areaction medium comprising an organic solvent and water having dissolvedtherein a basic salt. The amide thus produced is oxidized to providebenzhydrylsulphinylacetamide, commonly known as modafinil.

BACKGROUND OF THE INVENTION

Lafon disclosed modafinil and other similar compounds in U.S. Pat. No.4,177,290 as having pharmaceutical activity on the central nervoussystem. In a typical prior art process, benhydrylthioacetic acid ishalogenated with thionyl chloride. The chloride is then converted to theamide in methylene chloride with ammonia. The amide is then oxidizedwith hydrogen peroxide to provide benzhydrylsulphinylacetamide. Otherderivatives of modafinil as well as methods of preparation andpurification are disclosed in U.S. Pat. No. 4,127,722. However, theamide appears to be the compound of choice among the many derivativesnow known.

Interest in the Lafon compounds has increased in recent years becausethese compounds have been discovered to have beneficial effects in thetreatment of a wide variety of diseases in mammals including humans.Although first noted as a treatment for narcolepsy, more recent patentsand technical publications have listed such compounds as beneficial inthe treatment of Parkinson's disease, urinary incontinence, Alzheimer'sdisorder, ischemia and stroke. As the use of these compounds increasedso has the demand for greater volumes while maintaining the higheststate of purity and also avoiding process chemicals of highenvironmental risk.

Numerous substituted thioacetamides are disclosed in U.S. Pat. No.6,492,396 to Bacon et al. In one syntheses scheme benzhydrol isconverted to a benzhydrylthiol by reaction with thiourea that is thenconverted by hydrolysis to a thiouronium moiety. Subsequently, thethiouronium is converted to an acid with chloroacetic acid. Thebenzhydrylthioacetic acid is treated in various ways depending upon thedesired derivative. To prepare the amide the acid is reacted withammonia or an appropriate amine in an organic solvent such astetrahydrofuran or methylene chloride. Other thioacetamide derivativesare obtained by employing N-methylmorpholine and a thioacetic acid indimethylformamide (DMF).

A procedure for the preparation of an acetamide intermediate for theproduction of modafinil is disclosed in published U.S. application Ser.No. 2002/0183552. According to this application a three-step procedurefor preparing modafinil is disclosed starting with benzhydrol(diphenylmethanol) that is employed to prepare thebenzhydrylthiocarboxamidine salt by reaction with thiourea in hydrogenbromide. The bromide salt is then reacted with chloroacetamide inaqueous sodium hydroxide to produce diphenylmethylthioacetamide. Theacetamide may then be oxidized by conventional means to producemodafinil. Typically, the oxidation is provided by a reaction withhydrogen peroxide in glacial acetic acid.

Because of the growing demand for large quantities of modafinil in ahighly pure state there is needed a process for preparing the productefficiently without need for undesirable starting materials orby-products. In particular the production of the acetamide intermediateis particularly in need of improvement although given some degree ofattention in the art as indicated above.

SUMMARY OF THE INVENTION

In accordance with this invention there is provided a novel process forthe preparation of benzhydrylthioacetamide by the reaction of ahaloacetamide with the reaction product of thiourea and benzhydrol. Theimproved process is conducted in a solvent comprising water, havingdissolved therein a basic salt and a water miscible organic solvent. Theresulting benzhydrylthioacetamide is provided in high yield and purityand can be oxidized to provide the pharmaceutical modafinil.

The process of this invention provides improved yield and purity overknown processes. The water miscible organic solvent provides the dualfunction of providing a solvent for the starting organic material whilealso providing a convenient reaction medium allowing low temperaturereactions to take place.

DETAILED DESCRIPTION OF THE INVENTION

The pharmaceutical modafinil is conveniently prepared in three stepsincluding the novel step of this invention wherein DMF and a basic saltis employed. First, benzhydrol 1 is reacted with thiourea 2 to provide areaction product that is sometimes termed thebenzhydrylthiocarboxamidine salt 3. This reaction is carried out inwater in the presence of hydrogen bromide at a temperature of about 90°C. A solid benzhydrylthiocarboxamidine bromide salt precipitates. Thereaction may be described structurally as follows:

In the second step, the benzhydrylthiocarboxamidine bromide 3 salt iswashed with water then placed in a reaction vessel together withchloroacetamide 4, a basic salt, DMF, and water. This mixture is stirredto dissolve the bromide salt and to allow it to react at or near roomtemperature. Although the reaction is described with respect to thebromide salt, any other suitable salt may be employed. When the reactionis completed the reaction mixture is diluted with water and a solidprecipitate is separated. When washed with water,benzhydrylthioacetamide 5 is obtained in high yield and purity. Thereaction may be described structurally as follows:

In the third step of the procedure to obtain modafinil in accordancewith this invention benzhydrylthioacetamide 5 is dissolved in aceticacid and hydrogen peroxide is slowly charged to the solution whilecooling to control the exothermic reaction. Typically the temperature ismaintained below 22° C. to prevent undesired side reactions. After thereaction is completed, the product is isolated by diluting the reactionmixture with water and separating the precipitate to obtain a cruderacemic benzhydrylsulphinylacetamide 6 (modafinil). The crude product istypically refined by recrystallization in a solvent or a mixture ofsolvents including chloroform to obtain highly pure pharmaceutical grademodafinil. The reaction may be described structurally as follows:

The term “alkali metal” encompasses lithium, sodium, potassium, cesiumand rubidium; and the term “alkaline earth metal” includes beryllium,magnesium, calcium, strontium and barium. Typically, the preferredalkali metals are sodium and potassium while the preferred alkalineearth metal salts are calcium and magnesium.

On small-scale reactions, the use of a water-soluble organic solvent andalkali metal carbonate produced the expected product in very highpurity. Unfortunately, upon increasing the scale, excessive amounts ofbyproducts were produced as well as extreme discoloration of theproduct.

In an attempt to determine which possible initial impurities could causethe large-scale deviation, it was found that excess amounts ofun-reacted thiourea from previous reactions impaired the desiredreaction path. It was also discovered that the minor presence of waterhad no detrimental effect on the reaction. In trying to assess themaximum limit of the water impurity, surprisingly it was found thatwater had an advantageous effect on the desired reaction path. Waterprevented a number of byproducts from being formed while still allowingthe desired reaction to proceed. Continued experiments using a watermiscible organic solvent and water with a basic salt demonstrated a veryefficient reaction at room temperature with excellent yields. It hasbeen found that the ratio of water miscible organic solvent to water inthe reaction medium can be in a wide range. Typically the volume ratioof water miscible organic solvent/water is in the range of from about9/1 to about 1/9 and preferably from about 2/1 to about 1/1. The mostpreferred range is about 3/2.

Any suitable water miscible organic solvents can be employed in theprocess of this invention. The water miscible organic solvent must havesome degree of solvating power with respect to the organic startingmaterial benzhydrylthiocaboxamidine salt. Typically, such solventsinclude acetone and lower alkanols such as methanol, ethanol, butanol,sec-butyl alcohol and tert-butyl alcohol. However, it has been foundthat dimethylformamide (DMF) is particularly useful as well as otherwater miscible amides.

The process of this invention, employing a water miscible organicsolvent/water reaction medium containing a basic salt, can be run atroom temperature and produces isolated yields in the range of about 97%(based upon HPLC analysis) with the amount of impurities at less than1%. Such results represent significant yield improvements as well as amore efficient process compared to all other known methods. This processeliminates a process step and the use of thionyl chloride and benzene incomparison to the '290 patent. The process of this invention alsoeliminates the use of high temperatures, corrosive solutions, andbyproducts, while still producing higher yields with very low impuritiescompared to the prior art processes such as those that employ sodiumhydroxide with haloacetamide in the above described publishedapplication.

Any number of basic salts can be employed in the process of thisinvention. Salts may be employed that may only be slightly soluble inwater. However, the presence of the salt in the reaction medium remainseffective to promote the reaction in the particulate form. Thus the term“water soluble” as employed herein includes material only slightlysoluble in water. In particular, it is preferred to employ ammonium,alkali metal salts or alkaline earth metal salts. In particular, thesodium salt is preferred and the potassium salt is even more preferred.The anion of the salt is typically a sulfate, sulfide, phosphate,bicarbonate, nitrate, phosphonate, phosphinate and preferably acarbonate. Typical salts included in the above description of watersoluble salts are sodium sulfate, calcium sulfate, magnesium sulfate,sodium sulfide, magnesium sulfide, calcium sulfide, sodium phosphate,magnesium phosphate, calcium phosphate, potassium phosphate, sodiumbicarbonate, calcium bicarbonate, magnesium bicarbonate, sodium nitrate,calcium nitrate, magnesium nitrate, sodium phosphonate, potassiumphosphonate, magnesium phosphonate, calcium phophonate, sodiumphosphinate, potassium phosphinate, calcium phosphinate, magnesiumphosphinate, potassium sulfate, potassium sulfide, potassiumbicarbonate, potassium nitrate, potassium tripolyphosphate, sodiumtripolyphosphate, sodium thiophosphate, potassium citrate,tetrapotassium pyrophosphate, ammonium phosphate, ammonium chloride,ammonium sulfate, ammonium bicarbonate, ammonium phosphinate, ammoniumphosphonate and the like. Potassium carbonate is preferred because it isreadily soluble in water.

The process of this invention has been found to be particularlyadvantageous over the prior art sodium hydroxide process. Said prior artprocess requires higher temperatures to help increase the yields sincelower temperatures tend to produce significant amounts of impurities. Amilder basic solution was thought to be sufficient enough to promote thereaction and at lower temperature conditions. Water and potassiumcarbonate were initially used, but byproducts were still produced. In apreferred embodiment, a mixture of DMF and potassium carbonate solutionwas employed to help dissolve the starting reagent and promote a morestable pH during the reaction. The amount of basic salt, by weight ofthe total the starting reagent benzhydrylthiocarboxamidine bromide saltemployed in the process of this invention, is typically in the range offrom about 41% to about 200% and preferably in the range of from about82% to about 110% and most preferably in the range of from about 95% toabout 105%.

In another aspect of this invention is the clean up of the finalproduct, modafinil. It has been found that the final product was bestpurified by mixing it with chloroform. The preferred method is to thenrefluxing the mixture for a short period of time. The refluxed mixtureis then cooled to a relatively low temperature, filtered and washed toprovide a highly pure modafinil product. The use of methanol and/ormethanol:/water solvent as disclosed in the original '290 patent topurify the modafinil was found to be inadequate or inefficient inobtaining pharmaceutically pure modafinil. Similar alcohol solvents suchas ethanol and propanol also gave similar results wherein severalimpurities were significantly greater than 0.1%. Modafinil was onlymildly soluble, at best, in alcoholic solvents even at refluxtemperatures. Many impurities were also very insoluble in alcoholicsolvents and were thus retained in modafinil. In many cases 1 g of crudemodafinil required a minimum of 8 ml of methanol to be completelydissolved at reflux temperature. When filtered at room temperature, manyimpurities were only moderately reduced.

It also been found that excellent purification of modafinil can beachieved by mixing the crude modafinil product with a halo-organicsolvent such as dichloromethane, dichloroethane and preferablychloroform. Chloroform was initially believed to be a better solvent forthe clean-up procedure because it was slightly acidic in comparison toalcohols. Surprisingly, modafinil was also extremely insoluble inchloroform, but fortunately, the impurities were very soluble inchloroform. Major impurities in the crude modafinil product include themodafinil acid, modafinil sulfone acid, modafinil sulfone and unreactedstarting material, benzhydrylthioacetamide. Crude modafinil wasinitially mixed with chloroform in 1 g crude to 4 ml chloroform. It hasbeen found that the major impurities are substantially removed by thechloroform washing.

In a preferred embodiment a low boiling aliphatic solvent, preferablyheptane can be added in a ratio of about 2 ml of solvent to about 1 gcrude to help reduce the viscosity of the slurry. To address the problemof the viscous slurry, heptane can be charged first to the crude.Chloroform is then added to the stirred mixture slowly. A mild slurry,results. Heating the slurry to reflux further alleviates the viscosityto a simple solid/liquid mixture even when it was cooled to 5° C.allowing easy filtering with high yields. The slurry would become lessviscous only upon heating to reflux for about 30 minutes. Even thoughthe modafinil never completely dissolves in the solvent mixture, thecleaning procedure is effective. The solvent mixture is then cooled toabout 5° C. allowing the modafinil to precipitate fully after which itcan be filtered to obtain 92% to 97% recovery yield with −99.8% purityby weight (HPLC analysis), respectively. In this preferred embodimentany suitable low boiling aliphatic solvent such as pentane, hexane,heptane, or octane may be employed

The following examples are intended to illustrate the present inventionand are not to limit the claims in any manner. All of the percentagesare by weight unless otherwise indicated.

PREFERRED EMBODIMENTS OF THE INVENTION EXAMPLE 1 Preparation ofBenzhydrylthiocarboxamidine Bromide Salt

To a reaction vessel there was charged 82.63 g of thiourea, 150 ml ofHBr (48%) and 200 ml of water. Then, 100 g of benzhydrol were charged tothe mixture in the reaction vessel. The reaction mixture was thenrefluxed at 90° C. for 5 hr. The reaction mixture was then cooled toroom temperature and 100 ml of additional water were added to themixture followed by filtration. The crude solid residue was rinsed with75 ml and air dried to provide approximately 90% (molar) yield atgreater than 95% purity.

EXAMPLE 2 Preparation of Benzhydrylthioacetamide (a)

To a 500 ml. round bottom flask there were added 10 g ofbenzhydrylthiocarboxamidine bromide from Example 1, 3.46 g ofchloroacetamide, 10.7 g of potassium carbonate and 60 ml of DMF. Thismixture was stirred and 40 ml of water was added. An exothermic reactionoccurred and the temperature rose to 53° C. The reaction mixture wascooled to room temperature with continued stirring at room temperatureover night. The resulting solution exhibited a slight, minimal yellowtinge. Liquid chromatography indicated very little by product andstirring continued over night again. The reaction mixture was thencooled to 15° C. and slowly diluted with 200 ml water to maintain thetemperature below 22° C. A precipitate formed and the reaction mixturewas filtered to obtain 7.6 g of product Analysis by HPLC indicated thepresence of benzhydrylthioacetamide in 98% purity.

EXAMPLE 3 Preparation of Benzhydrylthioacetamide (b)

The procedure of Example 2 was repeated except the amount of reactantswas increased and the temperature more carefully controlled. To theround bottom flask were added 20 g of benzhydrylthiocarboxamidinebromide, 7 g of chloroacetamide, 21.5 g of potassium carbonate, and 100ml of DMF. The reaction mixture was cooled to 10° C. in an ice bath and40 g of water was slowly added so as to maintain the temperature of thereaction mixture below 22° C. The reaction mixture was stirred for 48 hrat room temperature. Then the reaction mixture was cooled to 10° C. andthen 300 ml of water were added to the reaction mixture whilemaintaining the mixture below 22° C. An exothermic condition wasobserved during the water addition. The reaction mixture was thenfiltered and the solid washed with 100 ml of water to obtain 15.3 g ofproduct. Analysis by HPLC indicated the product was 98% pure.

EXAMPLE 4 Preparation of Benzhydrylthioacetamide (c)

To a 2L three-necked flask there were added 197 g of crudebenzhydrylthiocarboxamidine bromide, (theoretical maximum 175 g), 61 gof chloroacetamide, 187 g of potassium chloride and 400 ml of DMF. Thereaction mixture was cooled to a range of from 10° C. to 15° C. Then,175 ml of water were charged to the reaction vessel while maintainingthe temperature of the reaction mixture below 20° C. The finaltemperature when finishing the water addition reached 12° C. The waterbath was removed and the reaction mixture stirred over night at roomtemperature. Then the reaction mixture was cooled to 5° C. and 1L ofwater was slowly charged to the reaction mixture. The reaction mixturewas filtered to collect a 135 g of precipitate (dry weight). Analysis byHPLC indicated that the product was 99% pure.

EXAMPLE 5 Preparation of Benzhydrylsulphinylacetamide

To a 500 ml three-necked round bottom flask was charged 50 grams ofbenzhydrylthioacetamide and 100 ml of acetic acid. The mixture wasstirred until all solids were dissolved and then the reaction mixturewas cooled to 15° C. There were then slowly added to the reactionmixture 25 ml of hydrogen peroxide solution (30%) in step-wise fashion(5-10 ml portions) while maintaining the temperature of the reactionmixture below 20° C. The reaction mixture was then stirred at roomtemperature (20° C.) or until the amide disappeared. There was thenadded 500 ml of water to the reaction mixture thereby precipitating theproduct. The reaction mixture was cooled to 15° C. and filtered. Thecrude solid product was then rinsed with 50 ml of water. The product wasthen purified by combining it with heptane (3.5 ml/1 g crude) and thenchloroform (7 ml/1 g of crude). The mixture was refluxed for 30 min. ata temperature of 70-75° C. The solution was slowly cooled to 10° C. withstirring and the solid precipitate then filtered and oven dried. Theyield was 85% (molar) and the purity was 99.8%.

Although the invention has been described in terms of specificembodiments which are set forth in considerable detail, it should beunderstood that this description is by way of illustration only and thatthe invention is not necessarily limited thereto since alternativeembodiments and operating techniques will become apparent to thoseskilled in the art in view of the disclosure. Accordingly, modificationsare contemplated which can be made without departing from the spirit ofthe described invention.

1. A process for the preparing of benzhydrylthioacetamide comprisingreacting benzhydrylthiocarboxamidine salt with haloacetamide in areaction medium comprising water, a water miscible organic solvent and awater soluble basic salt.
 2. The process of claim 1 wherein the basicsalt is selected from the group consisting of alkali metal and alkalineearth metal sulfates, sulfides, phosphates, carbonates, bicarbonates,nitrates, phosphonates and phosphinates.
 3. The process of claim 2wherein the haloacetamide is chloroacetamide.
 4. The process of claim 2wherein the basic salt is a potassium salt.
 5. The process of claim 4wherein the basic salt is a potassium carbonate salt.
 6. The process ofclaim 1 wherein the basic salt is present in a weight ratio tobenzhydrylthiocarboxamidine salt of from about 41 to about
 200. 7. Theprocess of claim 6 wherein the basic salt is present in the weight ratioof from about 82 to about
 110. 8. The process of claim 6 wherein thebasic salt is present in the weight ratio of about
 105. 9. The processof claim 1 wherein the volume ratio of water miscible organic solvent towater is in the range of from about 9/1 to 1/9.
 10. The process of claim9 wherein the volume ratio of water miscible organic solvent to water isin the range of from about 2/1 to 1/1.
 11. The process of claim 9wherein the volume ratio of water miscible organic solvent to water isabout 3/2.
 12. The process of claim 1 wherein the water miscible organicsolvent is selected from the group consisting of lower alkanols, acetoneand dimethylformamide.
 13. The process of claim 12 wherein the loweralkanol is selected from the group consisting of methanol, ethanol,butanol, sec-butyl alcohol, tert-butyl alcohol, and acetone.
 14. In aprocess for preparing modafinil comprising the following steps: reactingbenzhydrol with thiourea in the presence of hydrogen bromide to providebenzhydrylthiocarboxamidine bromide; reacting haloacetamide with theproduct of step a) to provide benzhydrylthioacetamide; oxidizing theproduct of step b) to obtain benzhydrylsulphinylacetamide; and theimprovement which comprises conducting the reaction of step b) in asolvent comprising a water miscible organic solvent, and water in thepresence of a basic salt.
 15. The process of claim 14 wherein the basicsalt is selected from the group consisting of alkali metal and alkalineearth metal sulfates, sulfides, phosphates, carbonates, bicarbonates,nitrates, phosphonates and phosphinates.
 16. The process of claim 14wherein the haloacetamide is chloroacetamide
 17. The process of claim 15wherein the basic salt is a potassium salt.
 18. The process of claim 17wherein the basic salt is a potassium carbonate salt.
 19. The process ofclaim 15 wherein the basic salt is present in a weight ratio tobenzhydrylthiocarboxamidine salt of from about 41 to about
 200. 20. Theprocess of claim 19 wherein the basic salt is present in the weightratio of from about 82 to about
 110. 21. The process of claim 20 whereinthe basic salt is present in the weight ratio of about
 105. 22. Theprocess of claim 14 wherein the volume ratio of water miscible organicsolvent to water is in the range of from about 9/1 to 1/9.
 23. Theprocess of claim 22 wherein the volume ratio of water miscible organicsolvent to water is in the range of from about 2/1 to 1/1.
 24. Theprocess of claim 22 wherein the volume ratio of water miscible organicsolvent to water is about 3/2.
 25. The process of claim 14 wherein thewater miscible organic solvent is selected from the group consisting oflower alkanols, acetone and dimethylformamide.
 26. A process for thepurification of modafinil which comprises contacting the crude modafinilwith a halo-organic solvent and then separating the modafinil from thesolvent.
 27. The process of claim 26 wherein the temperature of themixture of modafinil and halo-organic solvent is raised to a refluxtemperature.
 28. The process of claim 27 wherein the reflux temperatureis maintained for about 30 minutes.
 29. The process of claim 26 whereinthe halo-organic solvent is selected from the group consisting ofchloroform, dichloromethane, and dichloroethane.
 30. The process ofclaim 26 further including the step of adding an aliphatic solvent tothe mixture.
 31. The process of claim 30 wherein an aliphatic solvent isadded to modafinil prior to contacting the modafinil with thehalo-organic solvent and the temperature of the mixture is raised to thereflux temperature.
 32. The process of claim 31 wherein the refluxtemperature is maintained for about 30 minutes.
 33. The process of claim31 wherein the aliphatic solvent is selected from the group consistingof pentane, hexane, heptane and octane.
 34. The process of claim 30wherein the halo-organic solvent is chloroform and the aliphatic solventis heptane.